Fused bicyclic kinase inhibitors

Abstract

Compounds of Formula I, as shown below and defined herein: pharmaceutically acceptable salts thereof, synthesis, intermediates, formulations, and methods of disease treatment therewith, including treatment of cancers, such as but not limited to tumors driven at least in part by at least one of RON, MET, IR, IGF-1R, or ALK. This Abstract is not limiting of the invention.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is selected from H, C 1-3 aliphatic or —OC 1-3 aliphatic, either of which is optionally substituted with one or more halogen; 
         Y 1  and Y 2  are independently N or CH, except not more than one of Y 1  and Y 2  is N; 
         Y 3  is NH or CH; and when Y 3  is NH, then at least one of Y 1 , Y 2 , and Y 4  is N and Y 5  is C; 
         Y 4  is N or CH; 
         Y 5  is N or C, except not more than one of Y 4  and Y 5  is N; 
         R 1a , R 1b , R 1c , R 1d , R 1e  are each independently optional substituents selected from aliphatic, cyclic, —O-aliphatic, —O-cyclic, sulfide, sulfone, sulfoxide, amino, amido, carboxyl, acyl, ureido, —S-cyclic, any of which is optionally substituted, halogen, or nitrile; 
         R2 is H or an optional substituent. 
       
     
     
         2 . The compound or salt of  claim 1 , wherein:
 R a1 , R 1b , R 1c , R 1d , R 1e  are each independently selected from H, halo, —CN, C 1-6  alkyl, —CF 3 , —OCF 3 , —OCHF 2 , —OC 0-6 alkyl, —S(O) m C 1-6 alkyl, —SO 2 N(C 0-6 alkyl)(C 0-6 alkyl), —N(C 0-6 alkyl)(C 0-6 alkyl), —N(C 0-6 alkyl)C(═O)C 0-6 alkyl, —N(C 0-6 alkyl)C(═O)OC 0-6 alkyl, —N(C 0-6 alkyl)C(═O)N(C 0-6 alkyl)(C 0-6 alkyl), —C(═O)C 0-6 alkyl, —C(═O)OC 0-6 alkyl, —C(═O)N(C 0-6 alkyl)(C 0-6 alkyl), —O-heterocyclyl, —N(C 0-6 alkyl)-heterocyclyl, —N(C 0-6 alkyl)-heteroaryl, heterocyclyl, heteroaryl, 5-heteroaryl, or —O-heteroaryl; wherein the heterocyclyl is optionally substituted with oxo, C 1-6 alkyl, C(═O)OC 1-6 alkyl, C(═O)C 0-6 alkyl, C(═O)N(C 0-6 alkyl)(C 0-6 alkyl), SO 2 N(C 0-6 alkyl)(C 0-6 alkyl), or SO 2 C 1-6 alkyl; wherein the alkyl is optionally substituted with —OH, —OC 1-6 alkyl, N(C 0-6 alkyl)(C 0-6 alkyl), C(═O)N(C 0-6 alkyl)(C 0-6 alkyl), C(═O)OC 0-6 alkyl, C(═O)C 0-6 alkyl, heterocyclyl, or heteroaryl;   R 2  is selected from H, halo, —CN, —CF 3 , —NO 2 , C 0-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkylC 0-6 alkyl, C 3-6 heterocycloalkylC 0-6 alkyl, arylC 0-6 alkyl, or heteroarylC 0-6 alkyl, any of which is optionally substituted with one or more independent G 1  substituents;   or R 2  is selected from:   
       
         
           
           
               
               
           
         
         R 3  is selected from H, C 1-12 alkyl, R 4 O—C 2-12 alkyl-, R 4 R 5 N—C 2-12 alkyl-, R 4 S(O) m —C 2-12 alkyl, C 3-12 cycloalkylC 0-12 alkyl, C 3-12 cycloalkenylC 1-12 alkyl, heterocycloalkylC 0-12 alkyl, arylC 0-12 alkyl, heteroarylC 0-12 alkyl, C 1-12 alkylC 3-12 cycloalkyl, C 3-12 cycloalkylC 3-12 cycloalkyl, C 3-12 cycloalkenylC 3-12 cycloalkyl, heterocycloalkylC 3-12 cycloalkyl, arylC 3-12 cycloalkyl, heteroarylC 3-12 cycloalkyl, C 1-12 alkyl-heterocycloalkyl, C 3-12 cycloalkyl-heterocycloalkyl, C 3-12 cycloalkenyl-heterocycloalkyl, heterocycloalkyl-heterocycloalkyl, aryl-heterocycloalkyl, heteroaryl-heterocycloalkyl, —C(O)R a , R 4 O—C 0-12 alkylC(O)—, R 4 R 5 N—C 0-12 alkylC(O)—, R 4 S(O) m C 0-12 alkylC(O)—, —CO 2 R 4 , —C(O)NR 4 R 5 , —S(O) m R 4 , —SO 2 NR 4 R 5  or —C(S)OR 4 , any of which is optionally substituted with one or more independent G 2  substituents; 
         G 1  and G 2  are each independently selected from halo, —CN, —CF 3 , —OCF 3 , —NO 2 , oxo, R 6 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkylC 0-12 alkyl, heterocycloalkylC 0-12 alkyl, arylC 0-12 alkyl, heteroarylC 0-12 alkyl, —OR 6 , —S(O) m R 6 , —NR 6 R 7 , —SO 2 NR 6 R 7 , —C(O)R b , —C(O)NR 6 R 7 , —C(O)—C(O)NR 6 R 7 , —C(O)OR 6 , —C(O)—C(O)OR 6 , —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 ) n C(O)R b , —(CR 8 R 9 ) n C(O)OR 6 , —(CR 8 R 9 ) n C(O)NR 6 R 7 , —(CR 8 R 9 ) n S(O) 2 NR 6 R 7 , —(CR 8 R 9 ) n NR 6 R 7 , —(CR 8 R 9 ) n OR 6 , —(CR 8 R 9 ) n S(O) m R 6 , —NR 10 C(O)NR 6 R 7 , —NR 10 S(O) 2 NR 6 R 7 , or —NR 10 S(O)NR 6 R 7 , any of which is optionally substituted with one or more independent Q 1  substituents; 
         Q 1  is selected from halo, —CN, —NO 2 , oxo, —CF 3 , —OCF 3 , C 1-12 alkyl, arylC 0-12 alkyl, heteroarylC 0-12 alkyl, C 3-12 cycloalkylC 0-12 alkyl, heterocycloalkylC 0-12 alkyl, arylC 3-12 cycloalkyl, heteroarylC 3-12 cycloalkyl, heterocycloalkylC 3-12 cycloalkyl, C 3-12 cycloalkylC 3-12 cycloalkyl, C 1-12 alkyl-heterocycloalkyl, heterocycloalkyl-heterocycloalkyl, aryl-heterocycloalkyl, heteroaryl-heterocycloalkyl, —C(O)—C(O)NR 11 R 12 , —C(O)—C(O)OR 11 , —OC(O)R c , —NR 11 C(O)R c , —NR 11 S(O) 2 R 12 , —(CR 13 R 14 ) n C(O)R c , —(CR 13 R 14 ) n C(O)OR 11 , —(CR 13 R 14 ) n C(O)NR 11 R 12 , —(CR 13 R 14 ) n S(O) 2 NR 11 R 12 , —(CR 13 R 14 ) n NR 11 R 12 , —(CR 13 R 14 ) n OR 11 , —(CR 13 R 14 ) n S(O) m R 11 , —NR 15 C(O)NR 11 R 12 , —NR 15 S(O) 2 NR 11 R 12  or —NR 15 S(O)NR 11 R 12 , any of which is optionally substituted with one or more independent Q 2  substituents; 
         Q 2  is selected from halo, —CN, —OH, —NH 2 , —NO 2 , oxo, —CF 3 , —OCF 3 , —CO 2 H, —S(O) m H, C 1-12 alkyl, arylC 0-12 alkyl, heteroarylC 0-12 alkyl, C 3-12 cycloalkylC 0-12 alkyl, heterocycloalkylC 0-12 alkyl, arylC 3-12 cycloalkyl, heteroarylC 3-12 cycloalkyl, heterocycloalkylC 3-12 cycloalkyl, C 3-12 cycloalkylC 3-12 cycloalkyl, C 1-12 alkylheterocycloalkyl, heterocycloalkyl-heterocycloalkyl, aryl-heterocycloalkyl or heteroaryl-heterocycloalkyl, any of which is optionally substituted with one or more independent halo, —CN, —OH, —NH 2 , or C 1-10 alkyl which may be partially or fully halogenated, or —O—C 1-10 alkyl which alkyl may be partially or fully halogenated; 
         each R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R a , R b , and R c  is independently selected from H, C 1-12 alkyl or C 3-12 cycloalkyl, each optionally substituted by halo, —OCF 3 , or by —OC 0-3 alkyl, arylC 0-12 alkyl, heteroarylC 0-12 alkyl, C 3-12 cycloalkylC 0-12 alkyl, heterocycloalkylC 0-12 alkyl, arylC 3-12 cycloalkyl, heteroarylC 3-12 cycloalkyl, heterocycloalkylC 3-12 cycloalkyl, C 3-12 cycloalkylC 3-12 cycloalkyl, C 1-12 alkyl-heterocycloalkyl, heterocycloalkyl-heterocycloalkyl, aryl-heterocycloalkyl, or heteroaryl-heterocycloalkyl; 
         —NR 4 R 5 , —NR 6 R 7  and —NR 11 R 12  is each independently linear structure; or R 4  and R 5 , or R 6  and R 7 , or R 11  and R 12 , respectively, can be taken together with the nitrogen atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more heteroatoms selected from O, N, or S(O) m ; 
         —CR 8 R 9  or —CR 13 R 14  is each independently linear structure; or R 8  and R 9 , or R 13  and R 14 , respectively, can be taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more heteroatoms selected from O, N, or S(O) m ; 
         n=0-7; and 
         m=0-2. 
       
     
     
         3 . The compound or salt of  claim 1  or  2 , wherein:
 Y 1 , Y 2 , Y 3 , and Y 4  are CH; and Y 5  is N; or 
 Y 1  and Y 2  are CH; Y 3  is NH; Y 4  is N; and Y 5  is C. 
 
     
     
         4 . The compound or salt of  claim 1  or  2 , wherein:
 Y 1  is N; Y 2  and Y 4  are CH; Y 3  is NH; and Y 5  is C. 
 
     
     
         5 . The compound or salt of any one of  claims 1 - 4 , wherein X is selected from —OH, C 1-3 alkyl, or C 1-3 alkoxy. 
     
     
         6 . The compound or salt of any one of  claim 1 ,  3 , or  4 , wherein:
 R 1a  and R 1e  are each independently selected from halo, —CN, C 1-6 alkyl, —CF 3 , —OCF 3 , —OCHF 2 , or —OC 0-6 alkyl;   R 1b , R 1c , and R 1d  are each independently selected from H, halo, —CN, C 1-6 alkyl, —CF 3 , —OCF 3 , —OCHF 2 , or —OC 0-6 alkyl; wherein the alkyl is optionally substituted with —OH, —OC 1-6 alkyl, N(C 0-6 alkyl)(C 0-6 alkyl), C(═O)N(C 0-6 alkyl)(C 0-6 alkyl), C(═O)OC 0-6 alkyl, C(═O)C 0-6 alkyl, or heteroaryl;   R 2  is selected from halo, —CN, —CF 3 , —NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkylC 0-6 alkyl, C 3-6 heterocycloalkylC 0-6 alkyl, arylC 0-6 alkyl, or heteroarylC 0-6 alkyl, any of which is optionally substituted with 1-3 independent G 1  substituents;   or R 2  is selected from:   
       
         
           
           
               
               
           
         
         R 3  is selected from H, C 1-12 alkyl, R 4 O—C 2-12 alkyl-, R 4 R 5 N—C 2-12 alkyl-, R 4 S(O) m —C 2-12 alkyl-, C 3-12 cycloalkylC 0-12 alkyl, C 3-12 cycloalkenylC 1-12 alkyl, C 3-12 heterocycloalkylC 0-12 alkyl, arylC 0-12 alkyl, heteroarylC 0-12 alkyl, C 1-12 alkylC 3-12 cycloalkyl, C 3-12 cycloalkylC 3-12 cycloalkyl, C 3-12 cycloalkenylC 3-12 cycloalkyl, C 3-12 heterocycloalkylC 3-12 cycloalkyl, arylC 3-12 cycloalkyl, heteroarylC 3-12 cycloalkyl, C 1-12 alkylC 3-12 heterocycloalkyl, C 3-12 cycloalkylC 3-12 heterocycloalkyl, C 3-12 cycloalkenylC 3-12 heterocycloalkyl, C 3-12 heterocycloalkylC 3-12 heterocycloalkyl, arylC 3-12 heterocycloalkyl, heteroarylC 3-12 heterocycloalkyl, —C(O)R a , R 4 O—C 0-12 alkylC(O)—, R 4 R 5 N—C 0-12 alkylC(O)—, R 4 S(O) m C 0-12 alkylC(O)—, —CO 2 R 4 , —C(O)NR 4 R 5 , —S(O) m R 4 , —SO 2 NR 4 R 5  or —C(S)OR 4 , any of which is optionally substituted with 1-2 independent G 2  substituents; 
         each G 1  is independently selected from halo, —CN, —CF 3 , —OCF 3 , —NO 2 , R 6 , oxo, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkylC 0-12 alkyl, C 3-12 heterocycloalkylC 0-12 alkyl, arylC 0-12 alkyl, heteroarylC 0-12 alkyl, —OR 6 , —S(O) m R 6 , —NR 6 R 7 , —SO 2 NR 6 R 7 , —C(O)R b , —C(O)NR 6 R 7 , —C(O)—C(O)NR 6 R 7 , —C(O)OR 6 , —C(O)—C(O)OR 6 , —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 ) n C(O)R b , —(CR 8 R 9 ) n C(O)OR 6 , —(CR 8 R 9 ) n C(O)NR 6 R 7 , —(CR 8 R 9 ) n S(O) 2 NR 6 R 7 , —(CR 8 R 9 ) n NR 6 R 7 , —(CR 8 R 9 ) n OR 6 , —(CR 8 R 9 ) n S(O) m R 6 , —NR 10 C(O)NR 6 R 7 , —NR 10 S(O) 2 NR 6 R 7 , or —NR 10 S(O)NR 6 R 7 , any of which is optionally substituted with 1-2 independent Q 1  substituents; 
         each G 2  is independently selected from halo, —CN, —CF 3 , —OCF 3 , —NO 2 , C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, —OR 6 , —S(O) m R 6 , —NR 6 R 7 , —SO 2 NR 6 R 7 , —C(O)R b , —C(O)NR 6 R 7 , —C(O)—C(O)NR 6 R 7 , —C(O)OR 6 , —C(O)—C(O)OR 6 , —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 ) n C(O)R b , —(CR 8 R 9 ) n C(O)OR 6 , —(CR 8 R 9 ) n C(O)NR 6 R 7 , —(CR 8 R 9 ) n S(O) 2 NR 6 R 7 , —(CR 8 R 9 )NR 6 R 7 , —(CR 8 R 9 )OR 6 , —(CR 8 R 9 )S(O) m R 6 , —NR 10 C(O)NR 6 R 7 , —NR 10 S(O) 2 NR 6 R 7 , or —NR 10 S(O)NR 6 R 7 , any of which is optionally substituted with 1-2 independent Q 1  substituents; 
         each Q 1  is selected from halo, —CN, —NO 2 , oxo, —CF 3 , —OCF 3 , C 1-12 alkyl, C 3-7 cycloalkyl, —C(O)—C(O)NR 11 R 12 , —C(O)—C(O)OR 11 , —OC(O)Rc, —NR 11 C(O)Rc, —NR 11 S(O) 2 R 12 , —(CR 13 R 14 ) n C(O)R c , —(CR 13 R 14 ) n C(O)OR 11 , —(CR 13 R 14 ) n C(O)NR 11 R 12 , —(CR 13 R 14 ) n S(O) 2 NR 11 R 12 , —(CR 13 R 14 ) n NR 11 R 12 , —(CR 13 R 14 ) n OR 11 , —(CR 13 R 14 ) n S(O) m R 11 , —NR 15 C(O)NR 11 R 12 , —NR 15 S(O) 2 NR 11 R 12  or —NR 15 S(O)NR 11 R 12 ; 
         each R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R a , R b , and R c  is independently C 0-12 alkyl or C 3-7 cycloalkyl, each independently optionally substituted by halo, —OCF 3 , or —OC 0-3 alkyl; 
         each —NR 4 R 5 , —NR 6 R 7  and —NR 11 R 12  is independently linear in structure; or R 4  and R 5 , or R 6  and R 7 , or R 11  and R 12 , respectively, can be taken together with the nitrogen atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more heteroatoms selected from O, N, or S(O) m ; 
         each —CR 8 R 9  and —CR 13 R 14  is independently linear in structure; or R 8  and R 9 , or R 13  and R 14 , respectively, can be taken together with the carbon atom to which they are attached to form a 3-12 membered saturated or unsaturated ring, wherein said ring optionally includes one or more heteroatoms selected from O, N, or S(O) m ; 
         n=0-4; and 
         m=0-2. 
       
     
     
         7 . The compound or salt of any one of  claim 1 ,  3 , or  4 , having the formula: 
       
         
           
           
               
               
           
         
         wherein X is methyl, ethyl, or methoxy; 
         R 1a  and R 1e  are each independently selected from halo, —CN, C 1-6 alkyl, —CF 3 , —OCF 3 , —OCHF 2 , or —OC 1-6 alkyl; 
         R 1b  and R 1d  are each independently selected from H, halo, —CN, C 1-6 alkyl, —CF 3 , —OCF 3 , —OCHF 2 , or —OC 1-6 alkyl; 
         (i) R 2  is phenyl or pyridinyl, each substituted by one or more R 18  or G 1  wherein G 1  is  4-7 heterocycloalkyl optionally substituted with halogen, —OH, —OCH 3 , or C 1-3 alkyl, or G 1  is —C(O)NR 6 R 7 ; wherein each R 6  and R 7  is independently C 0-3  alkyl; or NR 6 R 7  defines a  4-7 heterocycloalkyl optionally substituted by C 1-6 alkyl; 
         or (ii) R 2  is pyrazolo optionally substituted by one or more R 18  or G 1  wherein G 1  is  4-6 heterocycloalkyl optionally substituted by halo, —R 6 , oxo, —S(O) m R 6 , —SO 2 NR 6 R 7 , —C(O)R b , —C(O)NR 6 R 7 , —C(O)—C(O)NR 6 R 7 , —C(O)OR 6 , or —C(O)—C(O)OR 6 ; or G 1  is C 3-6 cycloalkyl optionally substituted by halo, OH, —OR 6 , oxo, —S(O) m R 6 , —SO 2 NR 6 R 7 , —C(O)R b , —C(O)NR 6 R 7 , —C(O)—C(O)NR 6 R 7 , —C(O)OR 6 , or —C(O)—C(O)OR 6 ; or —C 1-6 alkyl which alkyl can be substituted by halo or —OC 0-5 alkyl; or G 1  is C 1-6 alkyl optionally substituted by —OH, —OR 6 , —R 6 , oxo, —NR 6 R 7 , —C(O)R b , —C(O)NR 6 R 7 , —C(O)—C(O)NR 6 R 7 , —C(O)OR 6 , —C(O)—C(O)OR 6 , —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 ) n C(O)R b , —(CR 8 R 9 ) n C(O)OR 6 , —(CR 8 R 9 ) n C(O)NR 6 R 7 , —(CR 8 R 9 ) n S(O) 2 NR 6 R 7 , —(CR 8 R 9 ) n NR 6 R 7 , —(CR 8 R 9 ) n OR 6 , —(CR 8 R 9 ) n S(O) m R 6 , —NR 10 C(O)NR 6 R 7 , —NR 10 S(O) 2 NR 6 R 7 , or —NR 10 S(O)NR 6 R 7 ; wherein each R 6 , R 7 , R 8 , R 9 , R 10 , and R b  is independently C 0-5 alkyl or C 3-6 cycloalkyl, each independently optionally substituted by halo, —OCF 3 , or —OC 0-3 alkyl; or NR 6 R 7  defines a  4-7 heterocycloalkyl optionally substituted by C 1-6 alkyl; R 18  is —R 6 , halo, —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 ) n C(O)R b , —(CR 8 R 9 ) n C(O)OR 6 , —(CR 8 R 9 ) n C(O)NR 6 R 7 , —(CR 8 R 9 ) n S(O) 2 NR 6 R 7 , —(CR 8 R 9 ) n NR 6 R 7 , —(CR 8 R 9 ) n OR 6 , —(CR 8 R 9 ) n S(O) m R 6 , —NR 10 C(O)NR 6 R 7 , or —NR 10 S(O) 2 NR 6 R 7 ; and wherein each m is independently 0-2; each n is independently 0-2. 
       
     
     
         8 . The compound or salt of  claim 7 , wherein:
 X is methyl;   R2 is pyrazole substituted by one or more R 18  or G1;   R 1a  and R 1e  are each independently selected from halo, —CN, —CF 3 , —OCF 3 , —OCHF 2 , or —OC 1-6 alkyl;   R 1b  and R 1d  are each independently selected from H, halo, —CN, —CF 3 , —OCF 3 , —OCHF 2 , or —OC 1-6 alkyl;   G 1  is  4-6 heterocycloalkyl optionally substituted by halo, —R 6 , oxo, —S(O) m R 6 , —SO 2 NR 6 R 7 , —C(O)R b , —C(O)NR 6 R 7 , —C(O)—C(O)NR 6 R 7 , —C(O)OR 6 , or —C(O)—C(O)OR 6 ;   or G 1  is  3-6 cycloalkyl optionally substituted by OH, —OR 6 , oxo, halo, —S(O) m R 6 , —SO 2 NR 6 R 7 , —C(O)R b , —C(O)NR 6 R 7 , —C(O)—C(O)NR 6 R 7 , —C(O)OR 6 , or —C(O)—C(O)OR 6 , or —C 1-6 alkyl which alkyl can be substituted by halo or —OC 0-5 alkyl;   or G 1  is C 1-6 alkyl optionally substituted by —OH, —OR 6 , —R 6 , oxo, halo, —NR 6 R 7 , —C(O)R b , —C(O)NR 6 R 7 , —C(O)—C(O)NR 6 R 7 , —C(O)OR 6 , —C(O)—C(O)OR 6 , —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 )C(O)R b , —(CR 8 R 9 )C(O)OR 6 , —(CR 8 R 9 )C(O)NR 6 R 7 , —(CR 8 R 9 )S(O) 2 NR 6 R 7 , —(CR 8 R 9 )NR 6 R 7 , —(CR 8 R 9 )OR 6 , —(CR 8 R 9 )S(O) m R 6 , —NR 10 C(O)NR 6 R 7 , —NR 10 S(O) 2 NR 6 R 7 , or —NR 19 S(O)NR 6 R 7 ;   wherein each R 6 , R 7 , R 8 , R 9 , R 10 , and R b  is independently C 0-5  alkyl or C 3-6 cycloalkyl, each independently optionally substituted by halo, —OCF 3 , or —OC 0-3 alkyl; or NR 6 R 7  defines a  4-7 heterocycloalkyl optionally substituted by C 1-6 alkyl; R 18  is —R 6 , halo, —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 ) n C(O)R b , —(CR 8 R 9 ) n C(O)OR 6 , —(CR 8 R 9 ) n C(O)NR 6 R 7 , —(CR 8 R 9 ) n S(O) 2 NR 6 R 7 , —(CR 8 R 9 ) n NR 6 R 7 , —(CR 8 R 9 ) n OR 6 , —(CR 8 R 9 ) n S(O) m R 6 , —NR 10 C(O)NR 6 R 7 , or —NR 10 S(O) 2 NR 6 R 7 ; and   each m is independently 0-2; and each n is independently 0-2.   
     
     
         9 . The compound or salt of  claim 7 , wherein:
 X is methyl;   R 2  is pyrazole substituted by one or more R 18  or G1;   R 1a  is Cl;   R 1e  is Cl, —OCH 3 , or —OCHF 2 ;   each R 1b  and R 1d  is independently H, F, or —OCH 3 ;   G 1  is  4-6 heterocycloalkyl optionally substituted by halo, R 6 , oxo, —S(O) m R 6 , —SO 2 NR 6 R 7 , —C(O)R b , —C(O)NR 6 R 7 , —C(O)—C(O)NR 6 R 7 , —C(O)OR 6 , or —C(O)—C(O)OR 6 ;   wherein each R 6 , R 7 , and R b  is independently C 0-5 alkyl or C 3-6 cycloalkyl, each independently optionally substituted by halo, —OCF 3 , or —OC 0-3 alkyl; or NR 6 R 7  defines a  4-7 heterocycloalkyl optionally substituted by C 1-6 alkyl; R 18  is —R 6 , halo, —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 ) n C(O)R b , —(CR 8 R 9 ) n C(O)OR 6 , —(CR 8 R 9 ) n C(O)NR 6 R 7 , —(CR 8 R 9 ) n S(O) 2 NR 6 R 7 , —(CR 8 R 9 ) n NR 6 R 7 , —(CR 8 R 9 ) n OR 6 , —(CR 8 R 9 ) n S(O) m R 6 , —NR 10 C(O)NR 6 R 7 , or —NR 19 S(O) 2 NR 6 R 7 ; and   m is 0-2.   
     
     
         10 . The compound or salt of  claim 7 , wherein:
 X is methyl;   R2 is pyrazole substituted by one or more R 18  or G1;   R 1a  is Cl;   R 1e  is Cl, —OCH 3 , or —OCHF 2 ;   each R 1b  and R 1d  is independently H, F, or —OCH 3 ;   G 1  is  3-6 cycloalkyl substituted by 0-2 substituents independently selected from —OH, —OR 6 , oxo, halo, —S(O) m R 6 , —SO 2 NR 6 R 7 , —C(O)R b , —C(O)NR 6 R 7 , —C(O)—C(O)NR 6 R 7 , —C(O)OR 6 , —C(O)—C(O)OR 6 , or —C 1-3 alkyl which alkyl can be substituted by halo or —OC 0-5 alkyl;   wherein each R 6 , R 7 , and R b  is independently C 0-5  alkyl or C 3-6 cycloalkyl; or NR 6 R 7  defines a  4-7 heterocycloalkyl optionally substituted by C 1-6 alkyl; R 18  is —R 6 , halo, —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 ) n C(O)R b , —(CR 8 R 9 ) n C(O)OR 6 , —(CR 8 R 9 ) n C(O)NR 6 R 7 , —(CR 8 R 9 ) n S(O) 2 NR 6 R 7 , —(CR 8 R 9 ) n NR 6 R 7 , —(CR 8 R 9 ) n OR 6 , —(CR 8 R 9 ) n S(O) m R 6 , —NR 10 C(O)NR 6 R 7 , or —NR 10 S(O) 2 NR 6 R 7 ; and   m is 0-2.   
     
     
         11 . The compound or salt of  claim 7 , wherein:
 X is methyl;   R2 is pyrazole substituted by one or more R 18  or G1;   R 1a  is Cl;   R 1e  is Cl, —OCH 3 , or —OCHF 2 ;   each R 1b  and R 1d  is independently H, F, or —OCH 3 ;   G 1  is C 1-6 alkyl substituted by 0-2 substituents independently selected from —OH, —OR 6 , —R 6 , oxo, halo, —NR 6 R 7 , —C(O)R b , —C(O)NR 6 R 7 , —C(O)—C(O)NR 6 R 7 , —C(O)OR 6 , —C(O)—C(O)OR 6 , —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 ) n C(O)R b , —(CR 8 R 9 ) n C(O)OR 6 , —(CR 8 R 9 ) n C(O)NR 6 R 7 , —(CR 8 R 9 ) n S(O) 2 NR 6 R 7 , —(CR 8 R 9 ) n NR 6 R 7 , —(CR 8 R 9 ) n OR 6 , —(CR 8 R 9 ) n S(O) m R 6 , —NR 10 C(O)NR 6 R 7 , —NR 10 S(O) 2 NR 6 R 7 , —NR 10 S(O)NR 6 R 7 , or  4-7 heterocycloalkyl optionally substituted by C 1-6 alkyl;   wherein each R 6 , R 7 , R 8 , R 9 , R 10 , and R b  is independently C 0-5  alkyl or C 3-6 cycloalkyl; or NR 6 R 7  defines a  4-7 heterocycloalkyl optionally substituted by C 1-6 alkyl; R 18  is —R 6 , halo, —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 ) n C(O)R b , —(CR 8 R 9 ) n C(O)OR 6 , —(CR 8 R 9 ) n C(O)NR 6 R 7 , —(CR 8 R 9 ) n S(O) 2 NR 6 R 7 , —(CR 8 R 9 ) n NR 6 R 7 , —(CR 8 R 9 ) n OR 6 , —(CR 8 R 9 ) n S(O) m R 6 , —NR 19 C(O)NR 6 R 7 , or —NR 10 S(O) 2 NR 6 R 7 ;   m is 0-2; and each n is independently 0-2.   
     
     
         12 . The compound or salt of  claim 7 , wherein:
 X is methyl;   R2 is pyrazole substituted by one or more R 18  or G1;   R 1a  is Cl;   R 1e  is Cl, —OCH 3 , or —OCHF 2 ;   R 1b  is F or —OCH 3 ;   R 1d  is H;   G 1  is C 1-6 alkyl substituted by 0-2 substituents independently selected from —OH, —OR 6 , —R 6 , oxo, halo, —NR 6 R 7 , —C(O)R b , —C(O)NR 6 R 7 , —C(O)—C(O)NR 6 R 7 , —C(O)OR 6 , —C(O)—C(O)OR 6 , —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 ) n C(O)R b , —(CR 8 R 9 ) n C(O)OR 6 , —(CR 8 R 9 ) n C(O)NR 6 R 7 , —(CR 8 R 9 ) n S(O) 2 NR 6 R 7 , —(CR 8 R 9 ) n NR 6 R 7 , —(CR 8 R 9 ) n OR 6 , —(CR 8 R 9 ) n S(O) m R 6 , —NR 10 C(O)NR 6 R 7 , —NR 10 S(O) 2 NR 6 R 7 , —NR 10 S(O)NR 6 R 7 , or  4-7 heterocycloalkyl optionally substituted by C 1-6 alkyl;   wherein each R 6 , R 7 , R 8 , R 9 , R 10 , and R b  is independently C 0-5  alkyl or C 3-6 cycloalkyl; or NR 6 R 7  defines a  4-7 heterocycloalkyl optionally substituted by C 1-6 alkyl; R 18  is —R 6 , halo, —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 ) n C(O)R b , —(CR 8 R 9 ) n C(O)OR 6 , —(CR 8 R 9 ) n C(O)NR 6 R 7 , —(CR 8 R 9 ) n S(O) 2 NR 6 R 7 , —(CR 8 R 9 ) n NR 6 R 7 , —(CR 8 R 9 ) n OR 6 , —(CR 8 R 9 ) n S(O) m R 6 , —NR 10 C(O)NR 6 R 7 , or —NR 10 S(O) 2 NR 6 R 7 ;   m is 0-2; and each n is independently 0-2.   
     
     
         13 . The compound or salt of  claim 7 , wherein:
 X is methyl;   R2 is pyrazole substituted by one or more R 18  or G1;   R 1a  is Cl;   R 1e  is Cl, —OCH 3 , or —OCHF 2 ;   R 1b  is F;   R 1d  is H;   G 1  is C 1-6 alkyl substituted by 0-2 substituents independently selected from —OH, —OR 6 , —R 6 , oxo, halo; —NR 6 R 7 , —C(O)R b , —C(O)NR 6 R 7 , —C(O)—C(O)NR 6 R 7 , —C(O)OR 6 , —C(O)—C(O)OR 6 , —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 ) n C(O)R b , —(CR 8 R 9 ) n C(O)OR 6 , —(CR 8 R 9 ) n C(O)NR 6 R 7 , —(CR 8 R 9 ) n S(O) 2 NR 6 R 7 , —(CR 8 R 9 ) n NR 6 R 7 , —(CR 8 R 9 ) n OR 6 , —(CR 8 R 9 ) n S(O) m R 6 , —NR 10 C(O)NR 6 R 7 , —NR 10 S(O) 2 NR 6 R 7 , —NR 10 S(O)NR 6 R 7 , or  4-7 heterocycloalkyl optionally substituted by C 1-6 alkyl;   wherein each R 6 , R 7 , R 8 , R 9 , R 10 , and R b  is independently C 0-3  alkyl or C 3-6 cycloalkyl; or NR 6 R 7  defines a  4-7 heterocycloalkyl optionally substituted by C 1-6 alkyl; R 18  is —R 6 , halo, —OC(O)R b , —NR 6 C(O)R b , —NR 6 S(O) 2 R 7 , —(CR 8 R 9 ) n C(O)R b , —(CR 8 R 9 ) n C(O)OR 6 , —(CR 8 R 9 ) n C(O)NR 6 R 7 , —(CR 8 R 9 ) n S(O) 2 NR 6 R 7 , —(CR 8 R 9 ) n NR 6 R 7 , —(CR 8 R 9 ) n OR 6 , —(CR 8 R 9 ) n S(O) m R 6 , —NR 10 C(O)NR 6 R 7 , or —NR 10 S(O) 2 NR 6 R 7 ;   m is 0-2; and each n is independently 0-2.   
     
     
         14 . The compound or salt of  claim 7 , wherein:
 X is methyl;   R 1a  and R 1e  are each independently selected from halo, —CN, C 1-6 alkyl, —CF 3 , —OCF 3 , —OCHF 2 , or —OC 1-6 alkyl;   R 1b  and R 1d  are each independently selected from H, halo, —CN, C 1-6 alkyl, —CF 3 , —OCF 3 , —OCHF 2 , or —OC 1-6 alkyl;   R 2  is phenyl or pyridinyl, each substituted by G 1 ;   G 1  is  4-7 heterocycloalkyl optionally substituted with halogen, —OH, —OCH 3 , or C 1-3 alkyl;   or G 1  is —C(O)NR 6 R 7 ; and   each R 6  and R 7  is independently C 0-3  alkyl or C 3-6 cycloalkyl; or NR 6 R 7  defines a  4-7 heterocycloalkyl optionally substituted by C 1-6 alkyl.   
     
     
         15 . The compound or salt of any one of  claims 1 - 14 , which is present as a material that is substantially free of its (S)-1-(phenyl)ethyl enantiomer when Y 4  or Y 5  of Formula I is N and substantially free of its (R)-1-(phenyl)ethyl enantiomer when Y 4  or Y 5  is not N. 
     
     
         16 . The compound or salt of any one of  claims 1 - 15 , which exhibits inhibition of MET in a cellular assay with an IC 60  of about 100 nM or less. 
     
     
         17 . The compound or salt of any one of  claims 1 - 16 , which exhibits inhibition of Ron in a cellular assay with an IC 50  of about 500 nM or less. 
     
     
         18 . The compound or salt of any one of  claims 1 - 17 , which is about 10-fold or more selective for MET over KDR. 
     
     
         19 . The compound or salt of any one of  claims 1 - 18 , which is about 10-fold or more selective for MET over Aurora kinase B. 
     
     
         20 . The compound or salt of  claim 1 , selected from any one of Examples 1-16 herein. 
     
     
         21 . A pharmaceutical composition comprising the compound or salt of any one of  claims 1 - 20 , formulated with or without one or more pharmaceutical carriers. 
     
     
         22 . Use of a therapeutically effective amount of a compound or salt of any one of  claims 1 - 20  in the manufacture of a medicament for treating a cancer mediated at least in part by MET and/or RON or which inhibition of RON and/or MET is effective. 
     
     
         23 . Use of a therapeutically effective amount of a compound or salt of any one of  claims 1 - 20  in the manufacture of a medicament for treating a cancer selected from bladder, colorectal, non-small cell lung, breast, or pancreatic, ovarian, gastric, head and neck, prostate, hepatocellular, renal, glioma, or sarcoma. 
     
     
         24 . The use of  claim 22  or  23 , wherein the compound or salt is a dual RON and MET inhibitor.